Recovery from experimental parkinsonism by intrastriatal application of erythropoietin or EPO-releasing neural precursors

Stephana Carelli; Toniella Giallongo; Cristina Viaggi; Elisa Latorre; Zuzana Gombalova; Andrea Raspa; Massimiliano Mazza; Francesca Vaglini; Anna Maria Di Giulio; Alfredo Gorio

doi:10.1016/j.neuropharm.2017.03.035

Recovery from experimental parkinsonism by intrastriatal application of erythropoietin or EPO-releasing neural precursors

Neuropharmacology. 2017 Jun:119:76-90. doi: 10.1016/j.neuropharm.2017.03.035. Epub 2017 Apr 1.

Affiliations

¹ Laboratories of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. Electronic address: [email protected].
² Laboratories of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy.
³ Dipartimento di Ricerca Traslazionale e Delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Italy.
⁴ Experimental Oncology Department, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
⁵ Laboratories of Pharmacology, Department of Health Sciences, University of Milan, Milan, Italy. Electronic address: [email protected].

PMID: 28373075
DOI: 10.1016/j.neuropharm.2017.03.035

Abstract

An extensive literature has shown a powerful neuroprotective action of Erythropoietin (EPO) both in vivo and in vitro. This study shows that EPO, whether ectopically administered or released by neural precursors, does reverse MPTP-induced parkinsonism in mice. Unilateral stereotaxic injection of 2.5 × 10⁵ erythropoietin-releasing neural precursor cells (Er-NPCs) rescued degenerating striatal dopaminergic neurons and promoted behavioral recovery as shown by three independent behavioral tests. These effects were replicated through direct intrastriatal administration of recombinant human EPO. At the end of the observational period, most of the transplanted Er-NPCs were vital and migrated via the striatum to reach Substantia Nigra. The restorative effects appear to be mediated by EPO since co-injection of anti-EPO or anti-EPOR antibodies antagonized the positive outcomes. Furthermore, this report supports the neuroprotective action of EPO, which may also be achieved via administration of EPO-releasing cells such as Er-NPCs.

Keywords: Adult stem cells; Cell therapy; Erythropoietin; MPTP; Parkinson's disease; Regenerative medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
Animals
Antiparkinson Agents / pharmacology
Antiparkinson Agents / therapeutic use
Arabidopsis Proteins / metabolism
Corpus Striatum / drug effects*
Corpus Striatum / physiology
Disease Models, Animal
Dopamine Plasma Membrane Transport Proteins / metabolism
Erythropoietin / metabolism
Erythropoietin / pharmacology*
Erythropoietin / therapeutic use*
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Intramolecular Transferases / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity / drug effects
Motor Activity / physiology
Muscle Strength / drug effects
Neural Stem Cells / metabolism
Neural Stem Cells / transplantation*
Parkinsonian Disorders / chemically induced
Parkinsonian Disorders / drug therapy*
Parkinsonian Disorders / surgery
Recovery of Function / drug effects*
Treatment Outcome
Tyrosine 3-Monooxygenase / metabolism

Substances

Antiparkinson Agents
Arabidopsis Proteins
Dopamine Plasma Membrane Transport Proteins
Erythropoietin
Green Fluorescent Proteins
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Tyrosine 3-Monooxygenase
Intramolecular Transferases
marneral synthase, Arabidopsis